Protection of myocardial tissue from apoptotic cell death and maladaptive hypertrophic remodeling are valid approaches to inhibit pathogenesis and slow the transition to heart failure. Despite increasingly detailed and specific knowledge of survival signaling pathways in the myocardium, the potential promise of beneficial interventional approaches using this knowledge remains unfulfilled. This failure stems, in part, from limitations in our current understanding of how cardiomyocytes interpret extracellular stimuli translate this into advantageous survival signaling in an appropriately regulated fashion. The long term goal of this study is to understand molecular mechanism(s) responsible for cardioprotective signaling in cardiomyocytes. The goal of this proposal is to demonstrate that myocardial signaling through Akt kinase can be manipulated beneficially to enhance cardiomyocyte survival and inhibit cardiomyopathic damage without pathologic side effects. Specifically, experiments are designed to define and optimize mechanisms to promote nuclear accumulation of Akt together with demonstration of efficacy at inhibiting cardiomyopathic remodeling. The hypothesis is that nuclear accumulation of Akt can be induced and controlled in order to inhibit cardiomyopathic changes in response to pathologic insults. Specific aims of the proposal will demonstrate that: 1) nuclear Akt accumulation mediates anti-hypertrophic effects, 2) accumulation of Akt in the nucleus is critical for beneficial cardioprotective action, 3) acute expression of nuclear-targeted Akt potentiates recovery from cardiomyopathic insults, and 4) nuclear accumulation of Akt is mediated by the C-LIM proteins zyxin and paxillin. The innovative approach employed will involve molecular, biochemical, and microscopic analyses of cultured cardiomyocytes and mouse models manipulated to optimize nuclear accumulation of Akt by cardioprotective stimuli, recombinant adenoviruses, and genetically engineered transgenic mouse lines. The significance of these studies is to establish the mechanism of Akt-mediated cardioprotective signaling in cardiomyocytes, define the mechanism of Akt-nuclear trafficking, and demonstrate the efficacy of interventional approaches to regulate Akt-mediated signal transduction and enhance cardiomyocyte survival in an appropriately beneficial fashion.